Background: In metastatic castrate resistant prostate cancer (mCRPC), the oral treatments of enzalutamide (ENZ) and abiraterone (AA) are used interchangeably because there are few large-scale comparative studies of the therapies. However, both drugs have different mechanisms of action, AA being an androgen biosynthesis inhibitor and ENZ being an androgen receptor inhibitor, so there may be therapeutic variance between the two drugs based on their interactions with comorbid conditions like obesity. Obesity not only increases the risk of other comorbidities, like heart disease, diabetes, and stroke, but has also been implicated in the development of CRPC. Methods: Patients treated with abiraterone or enzalutamide from September 10, 2014 to June 2, 2017 in the Veterans Health Administration were identified via pharmacy records. Among this population, patients were separated into body mass index (BMI) categories for underweight ( < 18.5), normal (18.5 to < 25), overweight (25 to < 30), and obese ( > 30). Age, Charlson Comorbidity Index and mCRPC treatments were collected and analyzed for the primary outcome of survival via the Kaplan-Meier method. A multivariate Cox proportional hazard model was performed with the following variables: BMI, Charlson Comorbidity Index, age, Black race, treatment with bone-directed therapy, and baseline PSA. Results: In patients with BMI > 25, there was a significantly improved overall survival for treatment with ENZ (n = 1623) over AA (n = 2159), with medians of 30.0 and 27.0 months respectively (p = 0.002). There was no significant difference in survival for patients with BMI < 25 (p = 0.48), with median survival of 17.7 months for ENZ (n = 589) and 16.1 months for AA (n = 860). The overall survival difference between underweight (n = 113), normal (n = 1336), overweight (n = 1879), and obese (n = 1903) groups shows significant increase in survival with increasing BMI, with the median survival durations of 9.2, 15.9, 23.9, and 29.8 months respectively (p < 0.001). This finding was corroborated by the Cox proportional hazard model, with the data indicating an increased risk of death (aHR = 1.58; 95% CI: 1.29, 1.94; p< 0.001) with the underweight group and decreased risk with the overweight (aHR = 0.75; 95% CI: 0.69, 0.81; p< 0.001) and obese (aHR = 0.64; 95% CI: 0.59, 0.70; p< 0.001) groups. Conclusions: Treatment with ENZ was associated with longer survival for mCRPC patients with overweight and obesity (BMI > 25) over AA. Otherwise, for normal and underweight patients (BMI < 25), there was no significant difference in overall survival between the two drugs. Higher BMI is associated with improved survival, suggesting a protective effect of obesity in mCRPC patients. While the reason for this finding warrants further investigation, similar findings have been seen in obese patients in some hormone driven cancers, like breast cancer and myeloma.